Neurodegenerative disorders, e.g. Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy body (DLB) diseases, are diagnosed primarily by clinical presentations, limited laboratory investigations and, more recently, structural and functional neuroimaging analysis (Bacskai et al., J Cereb Blood Flow Metab, 2002. 22(9): p. 1035-41; Klunk et al., J Neuropathol Exp Neurol, 2002. 61(9): p. 797-805; and Small et al., J Mol Neurosci, 2002. 19(3): p. 323-7). However the diagnosis based on these approaches is unsatisfactory. As determined by pathological examination, diagnostic accuracy of various neurodegenerative diseases varies between 50% to 85% depending on the disease involved, the experience of physicians and the stages of the diseases (Jankovic et al., Arch Neurol, 2000. 57(3): p. 369-72; Hughes et al., Brain, 2002. 125(Pt 4): p. 861-70; Litvan et al., Arch Neurol, 1998. 55(7): p. 969-78; Rajput et al., Can J Neurol Sci, 1991. 18(3): p. 275-8; Hughes et al., J Neurol Neurosurg Psychiatry, 1992. 55(3): p. 181-4; and McKeith et al., Semin Clin Neuropsychiatry, 2003. 8(1): p. 46-57). The fact that the diagnosis cannot be made with reasonable certainty until the latter stages of the diseases possibly underlies the current state of clinical management, i.e. none of the available therapies, particularly those aimed at preventing disease's progression, is effective; this could simply be due to the fact that most neurons are already degenerated by the time diagnosis is made. It is also noteworthy that it is common for patients with various neurodegenerative diseases to go undetected using current approaches (Love et al., Histopathology, 2004. 44(4): p. 309-17).
Biomarkers are biological characteristics used to indicate or to measure disease risk, presence, and progression. Ideally, an optimal biomarker should be precise, reliable, inexpensive, as well as reflect the pathophysiological mechanisms of neurodegenerative diseases. Presently, no established diagnostic biomarkers can confirm AD, PD or DLB or monitor their progression with high sensitivity at high specificity. Furthermore, markers are most useful if they can detect at an early or even preclinical stages of diseases. In searching for biochemical markers in body fluids, including plasma, urine, and cerebrospinal fluid (CSF), only limited success has been achieved despite decades of research. It has been felt recently that this is largely due to the heterogeneity of all neurodegenerative diseases, i.e. several markers may be needed to detect subpopulations of patients (Olsson et al., Clin Chem, 2005. 51(2): p. 336-45).
The development of genomics, proteomics, and metabolomics has greatly enhanced the ability to discover multiple markers that are not only useful for diagnosis of AD, PD and DLB but also shed more lights on their pathogenesis. However, these studies are limited, as none has taken other neurodegenerative diseases into consideration, and in addition, very few studies have been performed using cases with pathological verification. The present invention addresses this need.
Relevant Literature
Bacskai et al., J Cereb Blood Flow Metab, 2002. 22(9): p. 1035-41; Klunk et al., J Neuropathol Exp Neurol, 2002. 61(9): p. 797-805; Small et al., J Mol Neurosci, 2002. 19(3): p. 323-7; Jankovic et al., Arch Neurol, 2000. 57(3): p. 369-72; Hughes et al., Brain, 2002. 125(Pt 4): p. 861-70; Litvan et al., Arch Neurol, 1998. 55(7): p. 969-78; Rajput et al., Can J Neurol Sci, 1991. 18(3): p. 275-8; Hughes et al., J Neurol Neurosurg Psychiatry, 1992. 55(3): p. 181-4; McKeith et al., Semin Clin Neuropsychiatry, 2003. 8(1): p. 46-57; Love et al., Histopathology, 2004. 44(4): p. 309-17; Olsson et al., Clin Chem, 2005. 51(2): p. 336-45; Zhang et al., Neurobiol Aging, 2005. 26(2): p. 207-27; and Zhang et al., J Alzheimers Dis, 2005. 7(2): p. 125-33.